Estimation of the influenza‐associated respiratory hospitalization burden using sentinel surveillance data, Lebanon, 2015–2020

Abstract Introduction Influenza epidemics cause around 3 to 5 million cases of severe illness worldwide every year. Estimates are needed for a better understanding of the burden of disease especially in low‐ and middle‐income countries. The objective of this study is to estimate the number and rate of influenza‐associated respiratory hospitalizations in Lebanon during five influenza seasons (2015–2016 to 2019–2020) by age and province of residence in addition to estimating the influenza burden by level of severity. Methods The severe acute respiratory infection sentinel surveillance system was used to compute influenza positivity from the influenza laboratory confirmed cases. The total of respiratory hospitalizations under the influenza and pneumonia diagnosis was retrieved from the Ministry of Public Health hospital billing database. Age‐specific and province‐specific frequencies and rates were estimated for each season. Rates per 100 000 population were calculated with 95% confidence levels. Results The estimated seasonal average of influenza‐associated hospital admission was 2866 for a rate of 48.1 (95% CI: 46.4–49.9) per 100 000. As for the distribution by age group, the highest rates were seen in the two age groups ≥65 years and 0–4 years whereas the lowest rate was for the age group 15–49 years. For the distribution by province of residence, the highest influenza‐associated hospitalization rates were reported from the Bekaa‐Baalback/Hermel provinces. Conclusion This study shows the substantial burden of influenza in Lebanon mainly on high‐risk groups (≥65 years and <5 years). It is crucial to translate these findings into policies and practices to reduce the burden and estimate the illness‐related expenditure and indirect costs.


| INTRODUCTION
According to the World Health Organization (WHO), the seasonal influenza epidemics cause annually around 3 to 5 million cases of severe illness and around 290 000 to 650 000 respiratory deaths mainly among high risk groups like older adults and children less than 5 years of age 1 causing, as a result, a significant economic burden.
There is also a considerable economic impact of influenza among other age groups presenting with mild to moderate clinical symptoms. This is due to the loss or decrease in productivity associated with the increase in worker absenteeism. 2 Nonpharmaceutical public health measures like social distancing, hand hygiene, and cough/sneezing etiquette are important for preventing respiratory diseases; however, vaccination remains the most important intervention for influenza prevention. 3 The Strategic Advisory Group of Experts on Immunization (SAGE) recommends influenza vaccination to certain high-risk groups to be administered each year to reduce the risk of serious complications that could lead to hospitalization and death. However, the influenza vaccine uptake remains low in several countries including countries of the WHO Eastern Mediterranean Region. 4 Therefore, it is critical to estimate the burden of disease to better understand the impact of the disease especially in vulnerable groups like young children and older adults. 5 This improved understanding of influenza disease burden also assist to inform evidencebased policies and decisions when allocating limited resources and planning preventive measures to limit the influenza transmission and reduce the costs thereof. 6 Burden of disease studies also enhance surveillance and analytical capacities of countries to be used during pandemics. 7 Some studies have been conducted worldwide to estimate the burden of influenza. Different approaches have been used to estimate the influenza burden and the different sections of the disease severity pyramid. Used methods depend on the available data sources and the type of calculated estimates. According to the available results, the highest influenza-associated hospital admission rates were reported among children less than 5 years and older adults ≥65 years but the effect of influenza on the other age groups could not be ignored. [8][9][10][11] Although, as per WHO, global estimates are needed for a better understanding of the burden of disease worldwide, 7 there is a paucity of reliable and up-to-date estimates on the burden of influenza at the global and regional levels especially in low and middle-income countries 12 where the impact of influenza is expected to be the highest. 7 Similarly, no such estimates are available in Lebanon, which is a country in the Eastern Mediterranean region with a population of 5 to 6 million inhabitants, based on the United Nations Population division (UNPD) data.
We aimed in this study to estimate the number and rate of influenza-associated respiratory hospitalization in Lebanon during five influenza seasons (2015-2016 to 2019-2020) by age and province of residence in addition to estimate the influenza burden by level of severity.

| Data sources
The main data sources used in this study were the severe acute respiratory infections (SARI) sentinel surveillance system and the MoPH hospital billing database.
The SARI sentinel surveillance system launched in 2015 by the Epidemiological Surveillance Unit (ESU) at the Lebanese Ministry of Public Health (MoPH) in collaboration with the WHO aims mainly to estimate morbidity of SARI in Lebanon, identify baseline figures and alert/outbreak thresholds, identify circulating influenza strains, and detect novel viruses. SARI cases were defined as acute respiratory infection patients with a history of fever or measured fever of ≥38 C and cough with onset of symptoms within the last 10 days and requiring hospitalization. 2  The second source of data used in this study was the MoPH hospital billing database, which includes data on all Lebanese patients admitted to hospitals with different diagnoses and covered by the MoPH. The International Classification of Diseases, Tenth Revision (ICD-10), coding system is used to code cases' discharge diagnoses in the database. J00-J99 codes refer to all diseases of the respiratory system while J09-J18 are used for influenza and pneumonia. 13 Of note, MoPH covers hospital bills for Lebanese who are not insured by any type of insurance and who are estimated to represent 52.3% of hospitalized Lebanese patients. 14,15 As for the population estimates, they were based on the UNPD figures stratified by age and year.

| Data preparation
Methodological analysis and calculations were based on WHO guidelines. 6 Data were analyzed for all seasons for the period between week 40 of 2015 and week 39 of 2020. The period between week 40 of 1 year and week 39 of the following year was considered one season. This window was selected based on findings of the influenza severity assessment conducted in Lebanon using the Pandemic Influenza Severity Assessment (PISA) tool. 16 Cases with missing age, date, and PCR result were excluded from the analysis. The following age groups were considered: 0-4, 5-14, 15-49, 50-64, and ≥65 years.
Surveillance data on counts of SARI cases and laboratory-confirmed influenza were extracted from the SARI sentinel system and stratified by age group. The age-stratified influenza positivity percentage was then calculated for each season of the studied period by dividing the number of influenza positive specimens by the total SARI tested specimens. Data on total hospitalization from the MoPH hospital billing database were requested under ICD-10 principal diagnosis codes for influenza/pneumonia (J09-J18). Cases with missing age were excluded from the analysis. Data were stratified by age and adjusted for MoPH hospital coverage to obtain the estimate of the total number of influenza/pneumonia associated hospitalizations in Lebanon for each season stratified by age group. The hospital billing database covers 52.3% of Lebanese patients, 14 and based on UNPD estimates and UNHCR data, we estimated that on average Lebanese accounted for 83% of the total population during the study period. 15

| Computed indicators
The following indicators were computed: The estimates of the influenza-associated respiratory hospitalizations and rates by age group and province of residence during the study period in addition to the seasonal average for each estimate. Distribution of influenza cases and rates by level of severity was also estimated.

| Estimation of influenza-associated respiratory hospitalizations and rates
Descriptive statistical methods were used to estimate influenzaattributable hospitalizations and rates. As sentinel surveillance sites were distributed throughout the country and the same case definitions and sampling guidelines were used, the catchment population of the sentinel sites was considered representative of the Lebanese population. Therefore, data from the different sentinel sites were pooled to compute a national disease burden estimate. 6 Age-specific frequencies and rates were estimated for each season. Rates per 100 000 population were calculated with 95% confidence levels. Total respiratory admission rates, including Influenza and pneumonia admissions were estimated for each age group and season by dividing the respiratory admissions by the population for each group. The influenza-associated hospitalizations and rates per age group and season were then estimated and adjusted for the sensitivity and specificity of the SARI case definition using the following formula: For each season, average estimates were also computed.

| Estimates by province of residence
Province-specific frequencies and rates were estimated for each season. Cases with missing province of residence were excluded from the analysis. The difference in the coverage of the hospital billing database by province was taken into account in the calculation. 15

| Burden of disease pyramid
The influenza disease burden pyramid tool was used to estimate influenza-associated deaths and mild influenza illness. This tool uses a multiplier-based approach to estimate the influenza disease burden across levels of severity using available data on influenza-associated hospitalizations or deaths. 18 For our study, the pyramid was generated using the estimated average age-specific influenza-associated hospitalizations over the five studied influenza seasons. In the tool, the mid-year 2018 and the default multiplier were selected. Further, the tool was used with no corrections and no expansion factors. The average seasonal influenza counts by age strata across level of severity were estimated from the pyramid tool and rates were computed thereafter.

| Ethical approval
Data received from all sources were anonymous. Further, the analysis in this study was based on surveillance data thus no ethical approval was needed.   (Table 1 and Figure 1).

| RESULTS
T A B L E 1 Estimates of influenza-associated respiratory hospitalization numbers and rates by season and age group, Lebanon, 2015-2020.

| DISCUSSION
This is the first study conducted in Lebanon to estimate the burden of influenza at the national level. Influenza-associated respiratory hospitalizations and rates were estimated by age group and province of F I G U R E 1 Average estimates of influenza-associated respiratory hospitalization rates by age group, Lebanon, 2015-2020.
T A B L E 2 Estimates of influenza-associated respiratory hospitalization numbers and rates by season and province of residence, Lebanon, 2015-2020. residence. The influenza burden by level of severity was also estimated. The influenza-associated respiratory hospitalization rate computed in this study for all age groups (48.1 per 100 000) is comparable to results of studies conducted in Egypt (44 per 100 000) 19 and Zambia 20 but higher than estimates of other countries like Canada (33 per 100 000), Portugal (19.4 per 100 000), Indonesia (13-19 per 100 000), Iran(29 per 100 000), and Oman(7.3 and 27.5 per 100 000). [9][10][11]21,22 As for the estimated mortality rate for all agegroups (5.8 per 100 000), it is comparable to the worldwide mortality estimate (5.9 per 100 000) but higher than estimates of the Eastern Mediterranean region (4.5 per 100 000). 23 When comparing our study results to the country-specific estimates of global studies, we find a lower estimated hospitalization rate in our study (48.1 per 100 000) compared with global estimates for Lebanon (145.9 per 100 000) and a higher mortality rate (5.8 per 100 000) compared with global estimates for Lebanon (0.6 per 100 000). 24 In our study, we estimated that 347 influenza-associated respiratory deaths occur each year (range: 11-720) in Lebanon. This is higher than the global country figures estimating the median seasonal influenza-associated respiratory deaths to be 109 (95% CI: 40-399). 24 Discrepancies between our study results and global estimates are due to the different approaches and data sources used in the two types of studies.
Differences in the burden of disease results between different studies are affected by the studied influenza seasons and the different approaches used, which depend on the available resources. In addition, some estimates are from high-income countries, which might not be comparable to those from low and middle income countries due to the difference in age distribution, nutrition status, prevalence of highrisk conditions, access to health care, and preventive measures mainly vaccination policies. 7 According to our study results, the highest burden of influenza hospitalization is reported in the high-risk groups mainly adults above 65 and children less than 5 years, which is consistent with other studies conducted in different countries in the world. [9][10][11] These results could be used to feed into evidence-based policies to increase vaccination uptake especially among high-risk groups.
As for the distribution by province of residence, our study shows that the highest rates are reported from the Bekaa and Baalback/ Hermel provinces that include around 16% of Lebanon's population and are known to be Lebanon's most important farming region. 25 Further studies are needed to understand whether this difference is related to differential healthcare seeking behaviors or a different prevalence of risk factors for severe influenza across provinces.
As for the burden of disease pyramid, it helps in estimating the influenza-associated deaths, critically ill cases, and mild/moderate

| CONCLUSION
This study shows the substantial burden of influenza in Lebanon mainly on high-risk groups (≥65 years old and <5). It is crucial to translate these findings into policies and practices to reduce the burden of the disease. It is also crucial to conduct further studies to estimate the illness-related expenditure and indirect costs in addition to the disease burden averted through vaccination mainly among high-risk groups identified in this study. Further studies are also needed to determine the risk factors for severe outcomes associated with influenza illness as well as conducting knowledge, attitude, and practice (KAP) studies on the disease and vaccine hesitancy.

ACKNOWLEDGMENTS
The authors would like to acknowledge the efforts of Majd Saleh in implementing the SARI surveillance system in Lebanon and coordinating the system's activities between 2014 and 2017. We would also like to thank Nadine Haddad for coordinating the activities of the SARI surveillance system between 2018 and 2020 and Rabiha Rachid for her collaboration in providing the Ministry of Public Health hospital billing data. We are also thankful to the country and regional offices of the World Health Organization for supporting the SARI surveillance system and the burden of disease activities. We finally thank all the reporting sites for their continuous collaboration with the MOPH.

CONFLICT OF INTEREST STATEMENT
The authors have no conflict of interest to declare.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.